Ontology highlight
ABSTRACT: Methods
We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.Results
We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.Conclusion
Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.
SUBMITTER: Ouarhache M
PROVIDER: S-EPMC8249271 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Ouarhache Maryem M Marquet Sandrine S Frade Amanda Farage AF Ferreira Ariela Mota AM Ianni Barbara B Almeida Rafael Ribeiro RR Nunes Joao Paulo Silva JPS Ferreira Ludmila Rodrigues Pinto LRP Rigaud Vagner Oliveira-Carvalho VO Cândido Darlan D Mady Charles C Zaniratto Ricardo Costa Fernandes RCF Buck Paula P Torres Magali M Gallardo Frederic F Andrieux Pauline P Bydlowsky Sergio S Levy Debora D Abel Laurent L Cardoso Clareci Silva CS Santos-Junior Omar Ribeiro OR Oliveira Lea Campos LC Oliveira Claudia Di Lorenzo CDL Nunes Maria Do Carmo MDC Cobat Aurelie A Kalil Jorge J Ribeiro Antonio Luiz AL Sabino Ester Cerdeira EC Cunha-Neto Edecio E Chevillard Christophe C
Journal of clinical immunology 20210303 5
Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are k ...[more]